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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among endothelial secretogogues prostacyclin (PGI2), nitric oxide (NO) and tissue plasminogen activator (t-PA) play a crucial role in maintaining thromboresistance, tone and structure of the vascular wall. Most receptor agonists, such as B2 kinin receptor agonists, or shear force produce a coupled release of all three secretogogues, and therefore interactions between them are to be expected. Essentially, PGI2 is a platelet suppressant, NO a vasodilator and t-PA a fibrinolytic agent. These and other properties of endothelial secretogogues supplement each other in protecting the cardiovascular system from injuries. It is not surprising that disturbances of the secretory function of endothelial cells are associated with atherosclerosis, diabetes, thrombosis or hypertension. Traditionally, PGI2, NO, t-PA or their substitutes are used individually for the treatment of peripheral arterial disease, angina pectoris or acute myocardial infarction. In light of recent findings, their joint administration can be advocated. For instance, NO donors will potentiate platelet-suppressant action of PGI2 analogues, whereas exogenous PGI2 or TXA2 synthase inhibitors (i.e. following increase in endogenous PGI2) will abolish a paradox of prothrombotic action of t-PA or streptokinase. The replacement therapy with PGI2, NO or t-PA should match as closely as possible the physiologically coupled release of these secretogogues.
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PMID:Interactions between endothelial secretogogues. 754 32

1. The vascular and hormonal effects of L- and D-arginine were compared in healthy subjects and in patients with insulin-dependent diabetes mellitus or untreated essential hypertension. 2. Infusion of L- or D-arginine (40 mumol/l) in the forearm vascular bed, sufficient to increase the local concentration approximately 20-fold, had no effect on blood flow or the vasodilator response to acetylcholine (30 and 100 nmol/min) in patients with insulin-dependent diabetes (n = 7) or essential hypertension (n = 7), or in age- and sex-matched control subjects (n = 7 in both groups). 3. Systemic infusion of 10 g of L-arginine (n = 5) or D-arginine (n = 3) increased plasma concentration of arginine approximately 20-fold without altering supine or erect haemodynamics. Increases in plasma insulin, prolactin and glucagon were seen with both enantiomers. The stereopurity of arginine was confirmed in a cell-culture assay system. 4. We conclude that, in healthy subjects and patients with essential hypertension or insulin-dependent diabetes, synthesis of nitric oxide within the vasculature is not limited by substrate availability. At high concentrations of arginine, non-stereospecific effects, including alterations in hormone concentration, occur. It remains to be determined whether these non-stereospecific hormonal changes might contribute to certain haemodynamic effects of arginine.
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PMID:Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect? 755 60

A combination of metabolic and vascular defects have been implicated in the pathogenesis of diabetic neuropathy. Animal studies have demonstrated that a reduction in nerve blood flow may be an important early defect and that vasodilators can prevent or ameliorate nerve dysfunction. The potential factors contributing to nerve ischaemia include structural defects in the endoneurial microvasculature together with rheological abnormalities, abnormalities in vasoactive agents which regulate nerve blood flow including nitric oxide and the eicosanoids, and alterations in tone of the autonomic innervation of the nerve vasculature. The principle metabolic defects which have been implicated include disruption of the polyol pathway, altered lipid metabolism, advanced glycosylated end-product formation, increased oxidative stress, and diabetes-induced defects in growth factors. The demonstration that activation of the polyol pathway in experimental diabetes may affect nerve blood flow, and conversely that vasoactive agents appear to be important in regulating some aspects of nerve metabolism, has highlighted the interdependence of the metabolic and vascular defects in the pathogenesis of this condition. Thus, selective intervention aimed at a key defect early in this cascade may subsequently correct a number of later abnormalities offering therapeutic hope in this chronic debilitating complication.
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PMID:The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. 755 77

NO, a simple molecule synthesized from L-arginine by NO synthases, has been identified to play an important role in cell communication, cell defense and cell injury. The half life of NO is very short because NO either reacts with superoxide anion (O2-), and/or binds to heme molecules or Fe-S groups present in proteins. The biological effects of NO depend on both the concentration of NO at the site of action as well as upon the specific location where NO is generated. Small quantities of NO are generated by cNOS such as that present in the vascular endothelium, while large quantities of nitric oxide are synthesized by iNOS in response to cytokines or bacterial products. Within the kidney NO generated by endothelial cNOS participates in the regulation of the glomerular microcirculation by modifying the tone of the afferent arteriole and mesangial cells (Fig. 4). In addition, NO generated by macula densa and the afferent arteriole control glomerular hemodynamics via TGF and by modulating renin release. Therefore NO is important in the physiologic regulation of glomerular capillary blood pressure, glomerular plasma flow and the glomerular ultrafiltration coefficient. Through its actions on glomerular pressures and flows, NO may also regulate the macro- and micromolecular traffic through the mesangium. Chronic NO insufficiency causes hypertension and glomerular damage and may be causally involved in the genesis of salt dependent hypertension. Increased NO production may be involved in the early pathogenic hemodynamic changes in diabetes and in the physiologic hemodynamic responses to normal pregnancy. Maintenance of the antithrombogenic properties of the endothelium is another important action of NO which inhibits platelet aggregation and adhesion. Large quantities of NO such as that synthesized by either glomerular cells or macrophages during glomerular inflammation may lead to glomerular injury. A better understanding of the physiology and pathophysiology of NO in the kidney will lead to the development of new therapeutic avenues.
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PMID:Glomerular actions of nitric oxide. 756 80

It has been postulated that cytokines may mediate the beta-cell destructive process causing insulin-dependent diabetes mellitus. The aim of this investigation was to study cytokine effects on pancreatic islet functions in vitro. For this purpose 5-7 days precultured (medium RPMI 1640 +/- 10% fetal calf serum) rat pancreatic islets were exposed for another 48 h to either culture medium alone or with addition of rat interferon-gamma (IFN-gamma; 1000 U/ml), or human tumor necrosis factor-alpha (TNF-alpha; 1000 U/ml) or a combination of the cytokines. After the culture period the islets were subjected to short-term experiments in the absence of cytokines. Neither the DNA nor the insulin content of the islets were affected by the cytokines alone or by the combination. The combination IFN-gamma + TNF-alpha caused a 5-fold increase in the medium nitrite accumulation, indicating induction of nitric oxide formation. It was found that IFN-gamma reduced medium insulin accumulation and basal insulin secretion at 1.7 mM glucose, without affecting the medium nitrite level. On the other hand, the islet glucose oxidation rate at 16.7 mM glucose and the insulin secretory response to 16.7 mM glucose was normal or even increased when examined after 48 h. TNF-alpha alone had no significant effects. In conclusion, a combination of the cytokines can induce nitric oxide formation and inhibition of insulin production in rat pancreatic islets. However, this effect appears not to be sustained. Moreover, IFN-gamma alone seems to induce changes not related to nitric oxide.
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PMID:Effects of prolonged exposure in vitro to interferon-gamma and tumour necrosis factor-alpha on nitric oxide and insulin production of rat pancreatic islets. 757 79

1. Nitric oxide (NO)-mediated neurotransmission is impaired in anococcygeus muscle from 8-week streptozotocin-induced diabetic rats. This study investigated the effects of insulin treatment, and the duration of diabetes on this impairment. In addition, the effect of in vitro exposure to elevated glucose has been investigated on NO-mediated relaxations, in muscles from untreated rats. 2. Relaxant responses to field stimulation (0.5-5 Hz, 10s train), sodium nitroprusside (SNP; 5 and 10 nM) and NO (1 and 3 microM) were significantly impaired in anococcygeus muscles from 8-week diabetic rats, compared to responses from control rats. Insulin treatment (5 u Lente day-1, s.c.) of diabetic rats prevented the development of this impairment. 3. Consistent with findings in 8-week diabetic rats, relaxation induced by field stimulation, SNP and NO were attenuated in tissues from 2-week and 4-week diabetic rats compared to corresponding control responses, whereas relaxations to papaverine (3 and 10 microM) were not reduced. In contrast, diabetes of 3-days duration did not affect relaxations to field stimulation, SNP or NO. 4. Incubation of anococcygeus muscles from untreated rats in medium containing elevated glucose (44.1 mM) for 6 h, significantly impaired relaxations to field stimulation compared to responses obtained after normal glucose (11.1 mM) incubation. Relaxations to SNP and to NO were not affected by 6 h exposure to elevated glucose. Similarly, incubation in hyperosmolar solutions containing mannose or sucrose for 6 h, impaired relaxations to field stimulation, but not to SNP or NO. 5. The results indicate that the diabetes-induced impairment of NO-mediated neurotransmission in the rat anococcygeus muscle develops between 3 days and 2 weeks after the induction of diabetes with streptozotocin. Prevention of the impairment by insulin treatment suggests that it is specific for the diabetic state. In addition, the impairment may be related to hyperglycaemia and the consequent rise in osmolarity, since in vitro exposure to high glucose as well as to other hyperosmolar media impaired NO-mediated relaxations to field stimulation.
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PMID:Effect of diabetes and elevated glucose on nitric oxide-mediated neurotransmission in rat anococcygeus muscle. 758 50

Nitric oxide (NO) is considered to contribute to the impairment of B cell function in insulin-dependent diabetes mellitus. The effects of compounds that release NO were tested on the membrane potential and ionic currents of mouse pancreatic B cells using intracellular microelectrodes and the whole-cell patch-clamp technique. S-Nitrosocysteine led to a concentration-dependent reduction of electrical activity induced by 15 mM glucose. At a concentration of 1 mM, S-nitrosocysteine cause a hyperpolarization of the plasma membrane with complete suppression of electrical activity. In about half of the cells tested, electrical activity reappeared during treatment with S-nitroso-cysteine or after wash-out. However, in the other cells the hyperpolarization was followed by a slow depolarization and electrical activity did not reappear. The perforated-patch whole-cell K+ATP current first increased and subsequently decreased again during exposure to 1 mM S-nitroso-cysteine. With 0.1 and 0.01 mM S-nitroso-cysteine, only the rise of the current amplitude was observed. S-nitroso-cysteine (1 mM) almost completely abolished the current through voltage-dependent Ca2+ channels (measured with Ba2+ as charge carrier). Like S-nitroso-cysteine, 100 microM sodium-nitroprusside, another donor, evoked a marked hyperpolarization of the membrane potential that was at least in part reversible. To further ascertain that the effect of S-nitroso-cysteine was mediated by NO, we tested the decomposition products of S-nitroso-cysteine. Nitrite and denitrosylated S-nitroso-cystein (1 mM) did not alter electrical activity of B cells, whereas cysteine (1 mM) caused a slight depolarization. It is concluded that exogenous NO evokes rapid changes of B cell function by influencing the activity of ion channels.
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PMID:The effects of nitric oxide on the membrane potential and ionic currents of mouse pancreatic B cells. 758 83

Erectile dysfunction occurs frequently in human diabetes, and it is sometimes associated with hypogonadism. These conditions also develop in a model of insulin-dependent (type I) diabetes, the BB/WORdp (diabetic prone) rat but have not yet been investigated in the model of insulin-resistant (type II) diabetes, the BBZ/WOR rat. It is also unknown whether diabetes-related impotence is due to reduced levels of the mediator of penile erection, nitric oxide, caused by a decrease of nitric oxide synthase (NOS) in the penis. To clarify these questions, groups (n = 5-6) of diabetic BB/WORdp (insulin-maintained) and BBZ/WOR rats were age-matched with diabetic-resistant BB/WORdr and non-diabetic BB/WORdp rats and submitted to determinations of serum glucose, testosterone, and penile reflexes (cups and flips). Erectile dysfunction was found in all of type I and in most of type II diabetic animals (glycemias of 25.0 and 31.1 mM), at the selected mean ages of 310 and 180 days old, respectively. This was evidenced by over 95% decreases of erectile reflexes in both types of diabetes and was accompanied by 75% reduction of serum testosterone. Soluble NOS activity was measured in penile tissue from the diabetic rats with impaired erectile reflexes and in the corresponding controls, by the (3H)-L-arginine/citrulline conversion assay. The neuronal NOS isoform (nNOS) content was determined by a semiquantitative western blot assay. Both types of diabetes showed a marked decrease of penile NOS activity (74 and 55%, respectively), and a lower reduction of penile nNOS content (47 and 33%, respectively). No endogenous NOS inhibitor was detected in the diabetic type I penile cytosol by cross-mixing NOS activity assays. Our data support a common etiology for erectile dysfunction present in rats with types I and II diabetes mellitus and suggest that the etiology is related to a decrease of penile NOS derived in part from serum androgen deficiency.
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PMID:Reduction of penile nitric oxide synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type II) rats with erectile dysfunction. 758 27

Both rat alveolar macrophages and a human macrophages cell line with characteristics of human tissue (e.g., alveolar) macrophages (THP-1) were found to inhibit the germination of Rhizopus spores. However, the conditions under which fungistatic activity occurs are different for these two cell types. The inhibition of Rhizopus spore germination by rat alveolar macrophages requires the activation of macrophages and the presence of serum and L-arginine. During rat alveolar macrophage-mediated fungistatic activity, L-arginine is oxidized to nitric. Human macrophage-mediated fungistatic activity is similar to that mediated by rat macrophages in terms of the serum requirement, but it does not require L-arginine. Human macrophages did not produce any nitrite detectable by the colorimetric assay. Their ability to inhibit germination was enhanced by the combination of endotoxin and gamma interferon. The inhibition of Rhizopus spore germination by rat alveolar macrophages is thus mediated by the generation of nitric oxide, whereas the mechanism of similar inhibition by human macrophages remains poorly understood. Serum samples from diabetic rats as well as from patients with diabetes or uremia decreased the inhibitory effect of macrophages on spore germination. Dialysis of the serum samples against a buffered salt solution antagonized this phenomenon, indicating that a low-molecular-weight factor in the sera of patients with diabetes or uremia may modulate local antifungal defense mechanisms. The absence of L-arginine-dependent nitrogen oxidation in human macrophages, compared with its presence in rat alveolar macrophages, under conditions during which fungistatic activity occurs suggests that this phenomenon is species specific.
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PMID:Human and rat macrophages mediate fungistatic activity against Rhizopus species differently: in vitro and ex vivo studies. 759 Oct 90

Plasma and vascular kinins stimulate the production of endothelium-derived nitric oxide, prostacyclin and hyperpolarizing factor (which regulates the function of vascular smooth muscle), and endothelial interactions with blood cells. The role of kinins in vasomotion is determined by the rate of production of the peptides by kininogenases and their degradation by kininases, in particular angiotensin-converting enzyme (ACE). Acute increases in plasma kinin levels during exercise or myocardial ischemia indicate that the metabolism of the peptides is fine tuned to the systemic or local metabolic demands. The release of endothelial vasodilators is impaired (or counterbalanced by the release of chemical or functional antagonists) in atherosclerosis, hypertension, diabetes, subarachidonic hemorrhage, and following postischemic injury. ACE-inhibitors potentiate the action of kinins and normalize endothelial function. In septic shock, hypotension triggered by overproduction of kinins leads to cardiovascular impairment and end-organ damage. Thus the balance in the metabolism of kinins modulates the control of blood flow by the endothelium.
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PMID:Kinins and endothelial control of vascular smooth muscle. 759 12


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